Stable compositions of famotidine and ibuprofen

ABSTRACT

Stable pharmaceutical compositions of famotidine and ibuprofen in a single unit dosage form are disclosed herein. The compositions comprise a famotidine core having a reduced or minimal surface area surrounded by a layer of ibuprofen. In some embodiments, the ibuprofen is in direct physical contact with the famotidine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/285,981, filed Oct. 31, 2011, incorporated herein by reference in itsentirety, which is a continuation of U.S. application Ser. No.12/324,808, filed Nov. 26, 2008, now U.S. Pat. No. 8,067,033,incorporated herein by reference in its entirety, which claims thebenefit of U.S. Application No. 60/991,628, filed Nov. 30, 2007,incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions containingibuprofen and famotidine, and finds application in the field ofmedicine.

BACKGROUND OF THE INVENTION

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has been usedin humans for nearly forty years. While generally regarded as safe,ibuprofen and other NSAIDs can cause gastritis, dyspepsia, and gastricand duodenal ulceration. Gastric and duodenal ulceration is aconsequence of impaired mucosal integrity resulting fromibuprofen-mediated inhibition of prostaglandin synthesis. Thisside-effect is a particular problem for individuals who take ibuprofenfor extended periods of time, such as patients suffering from rheumatoidarthritis and osteoarthritis.

The risk of developing gastric or duodenal ulceration can be reduced bycotherapy with the drug famotidine. Famotidine blocks the action of thehistamine type 2 (H2) receptor, leading to a reduction of acid secretionin the stomach. Reducing stomach acid with famotidine during treatmentwith certain nonsteroidal anti-inflammatory drugs is reported todecrease incidence of gastrointestinal ulcers (see Taha et al., 1996,“Famotidine for the prevention of gastric and duodenal ulcers caused bynonsteroidal anti-inflammatory drugs” N Engl J. Med 334:1435-9, andRostom et al., 2002, “Prevention of NSAID-induced gastrointestinalulcers” Cochrane Database Syst Rev 4:CD002296).

Although NSAID plus famotidine cotherapy reduces risk of developinggastric or duodenal ulceration, such therapies are not widely used. Oneexplanation for this observation is that patient compliance is moreproblematic with a regimen that requires administration of two separatedosage forms. Efforts to develop a single unit dosage form comprisingboth ibuprofen and famotidine have been successful (see co-pending U.S.application Ser. Nos. 11/489,275, filed Jul. 18, 2006, 11/489,705, filedJul. 18, 2006, and 11/779,204, filed Jul. 17, 2007), but were made morechallenging by the discovery that ibuprofen and famotidine arechemically incompatible. Moreover, those dosage forms that have beendescribed could be improved with respect to stability under “forceddegradation” or “accelerated” conditions of elevated temperature andhumidity. Forced degradation conditions are intended to accelerate theprocess of chemical degradation for a period of time and are used topredict the effect of storage under more benign conditions (e.g., roomtemperature) for a longer period of time.

There remains a need for new and improved unit dosage forms comprisingibuprofen and famotidine that exhibit exceptional stability under forceddegradation conditions. The present invention meets that need.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a pharmaceuticalcomposition, comprising (i) a core comprising a therapeuticallyeffective amount of famotidine, and (ii) a surrounding portioncomprising a therapeutically effective amount of ibuprofen in directphysical contact with the core, wherein the famotidine and the ibuprofenare in direct physical contact over a surface area that does not exceedan area calculated from the formula: (25 mm²) (3.75 mm²·x), where x isthe quantity (mg) of famotidine in the core, and wherein the compositionis stable for at least 1 month at 40° C. and 75% relative humidity.

In some cases, the core comprises famotidine in an amount from 24 mg to28 mg, and the shell comprises ibuprofen in an amount from 750 mg to 850mg. In other cases, the core comprises about 26.6 mg of famotidine. Insome embodiments, the core comprises famotidine in an amount from 24 mgto 28 mg, and the shell comprises ibuprofen in an amount from 575 mg to625 mg. In some embodiments, the core comprises famotidine in an amountfrom 12 mg to 14 mg, and the shell comprises ibuprofen in an amount from375 mg to 425 mg. In at least one embodiment, the ibuprofen is in theform of Ibuprofen DC 85™.

In some embodiments, the surface area of direct physical contact betweenthe famotidine and the ibuprofen does not exceed 120 mm². In someembodiments, the surface area of direct physical contact between thefamotidine and the ibuprofen does not exceed 100 mm². In at least oneembodiment, the surface area of direct physical contact between thefamotidine and the ibuprofen does not exceed 65 mm².

In some embodiments, the core is substantially spherical in shape. Inother embodiments, the core is substantially cylindrical in shape.

In another aspect, the present invention is directed to a pharmaceuticalcomposition, comprising (i) a core comprising from 24 mg to 28 mg offamotidine, and (ii) a surrounding portion comprising from 775 mg to 825mg of ibuprofen in direct physical contact with the core, wherein thefamotidine and the ibuprofen are in direct physical contact over asurface area that does not exceed 130 mm², and wherein the compositionis stable for at least 1 month at 40° C. and 75% relative humidity.

In at least one embodiment, the ibuprofen is in the form of Ibuprofen DC85™.

In some embodiments, the core is substantially cylindrical in shape andthe surface area of direct physical contact between the famotidine andthe ibuprofen does not exceed 120 mm². In some embodiments, the surfacearea of direct physical contact between the famotidine and the ibuprofendoes not exceed 115 mm². In some embodiments, the core is substantiallyspherical in shape and the surface area of direct physical contactbetween the famotidine and the ibuprofen does not exceed 100 mm².

DETAILED DESCRIPTION

I. Definitions

“Famotidine” refers to3-[2-(diaminomethyleneamino)thiazol-4-ylmethylthio]-N-sulfamoylpropionamidine,including the polymorphic forms designated Form A and Form B (see, e.g.U.S. Pat. Nos. 5,128,477 and 5,120,850) and their mixtures, as well aspharmaceutically acceptable salts thereof. Famotidine can be preparedusing art-known methods, such as the method described in U.S. Pat. No.4,283,408. Famotidine's properties have been described in the medicalliterature (see, e.g., Echizen et al., 1991, Clin Pharmacokinet.21:178-94).

“Ibuprofen” refers to 2-(p-isobutylphenyl) propionic acid (C₁₃H₁₈O₂),including various crystal forms and pharmaceutically acceptable salts.Two enantiomers of ibuprofen exist. As used herein in the context ofsolid formulations of the invention, “ibuprofen” refers to a racemicmixture or both enantiomers as well as racemic mixtures that containmore of one enantiomer than another (including, for example, mixturesenriched in the S-enantiomer), and enantiomerically pure preparations(including, for example, compositions substantially free of theR-enantiomer). Ibuprofen is available commercially, typically as aracemic mixture, and, for example, ibuprofen preparations with meanparticle sizes of 25, 38, 50, or 90 microns can be obtained from BASFAktiengesellschaft (Ludwigshafen, Germany). One useful ibuprofen productis a directly compressible formulation described in WO 2007/042445(incorporated herein by reference), a version of which is available fromBASF under the trade name Ibuprofen DC 85™. Ibuprofen's properties havebeen described in the medical literature (see, e.g., Davies, 1998,“Clinical pharmacokinetics of ibuprofen. The first 30 years” ClinPharmacokinet 34:101-54).

A “therapeutically effective amount” of ibuprofen is an amount ofibuprofen or its pharmaceutically acceptable salt which eliminates,alleviates, or provides relief of the symptoms for which it isadministered.

A “therapeutically effective amount” of famotidine is an amount offamotidine or its pharmaceutically acceptable salt which suppressesgastric acid secretion, or otherwise eliminates, alleviates, or providesrelief of the symptoms for which it is administered.

An “excipient,” as used herein, is any component of an oral dosage formthat is not an active pharmaceutical ingredient (i.e., ibuprofen and/orfamotidine). Excipients include binders, lubricants, diluents,disintegrants, coatings, barrier layer components, glidants, and othercomponents. Excipients are known in the art (see HANDBOOK OFPHARMACEUTICAL EXCIPIENTS, FIFTH EDITION, 2005, edited by Rowe et al.,McGraw Hill). Some excipients serve multiple functions or are so-calledhigh functionality excipients. For example, talc may act as a lubricant,and an anti-adherent, and a glidant. See Pifferi et al., 2005, “Qualityand functionality of excipients” Farmaco. 54:1-14; and Zeleznik andRenak, Business Briefing: Pharmagenerics 2004.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

A “compartment” in the context of a unit dosage form is a physicalregion of a tablet or other dosage form. Two components of a unit dosageform are distinct compartments if there exists a recognizabledemarcation between the two components, even though they may be indirect physical contact with one another.

The term “core,” as used herein, refers to a single interior compartmentof a unit dosage form comprising famotidine.

The term “shell,” as used herein, refers to an exterior compartment of aunit dosage form comprising ibuprofen, which completely surrounds thecore or famotidine compartment. As described herein, this exteriorcompartment may be over-coated for cosmetic or other reasons, inparticular embodiments.

The term “direct physical contact” refers to the absence of a barrierlayer between components or adjacent compartments of a unit dosage form.

The term “stable,” as used herein, refers to a composition in which theactive pharmaceutical ingredients (i.e., ibuprofen and famotidine) arepresent in an amount of at least 90%, and preferably at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%of the originally specified amount for each such ingredient, and no morethan 3%, and preferably no more than 2%, no more than 1%, no more than0.9%, no more than 0.8%, no more than 0.7%, or no more than 0.6%sulfamide is present after a specified period of time and underspecified conditions.

The term “about,” as used herein, is intended to indicate a range (e.g.,±10%) caused by experimental uncertainty, variations resulting frommanufacturing tolerances, or variations within the parameters of a labelclaim associated with a drug product.

The term “substantially,” as used herein with reference to the sphericalor cylindrical shape of the core of a pharmaceutical composition or unitdosage form refers to variability resulting from manufacturingtolerances, as well as intentional deviations from these precisegeometric shapes. For example, in a sphere the three axes are ofidentical length. In this context, the term “substantially” is intendedto indicate a tolerance for a deviation of ±5% in the length of one ortwo of the axes in relation to the third axis, thus encompassing anoblongation or other variation of a spherical shape. In the context of acylinder, the term “substantially” is intended to indicate a tolerancefor a deviation of ±5% in the diameter of the cylinder along its length.For example, if the diameter increases from either end of the “cylinder”to a central position, the shape may be more appropriately referred toas a “barrel,” but is still intended to be encompassed by the phrase“substantially cylindrical in shape.”

II. Tablet-in-Tablet Compositions

Pharmaceutical compositions in accordance with the present inventioncomprise ibuprofen and famotidine in a single unit dosage form. In oneaspect, the present invention relates to an oral dosage form comprisingibuprofen and famotidine, and optionally, one or more pharmaceuticallyacceptable excipients. It has been discovered that by reducing thesurface area of direct physical contact between ibuprofen andfamotidine, one can attain an unexpectedly profound increase instability relative to alternative designs (e.g., barrier-coatedfamotidine multiparticulates in a matrix comprising ibuprofen).Moreover, using the design of the present invention, the barrier layercan be omitted without sacrificing stability.

In one embodiment of the present invention, the pharmaceuticalcomposition comprises a core comprising a therapeutically effectiveamount of famotidine, and a surrounding portion comprising atherapeutically effective amount of ibuprofen in direct physical contactwith the core, e.g., a tablet-in-tablet formulation. The surface areaover which the famotidine and ibuprofen are in direct physical contactis controlled so as not to exceed an area calculated from the followingformula (Formula (I)):(25 mm²)+(3.75 mm²·x),where x is the quantity, in milligrams, of famotidine in the core. Thispharmaceutical formulation provides a composition which is stable for atleast one month at 40° C. and 75% relative humidity.

In other embodiments, the surface area of the famotidine core is asdescribed above with reference to Formula (I), but rather than being indirect physical contact with the ibuprofen shell, a barrier layer isinterposed between the two compartments. Generally, the barrier layermay comprise a water-soluble, pH independent film that promotesimmediate disintegration for rapid release of the famotidine core.Materials that can be used for readily soluble films are well known inthe art and include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, and ethyl cellulose; methacrylicpolymers, amino-alkylmethacrylate copolymers (e.g. Eudragit™E),polyvinyl acetate phthalate and polyvinyl alcohol (PVA). A plasticizer(e.g., triacetin, diethyl phthalate, tributyl sebacate or polyethyleneglycol) may also be included. The barrier layer may include ananti-adherent or glidant (e.g., talc, fumed silica or magnesiumstearate) and colorants such as titanium dioxide, iron oxide basedcolorants or others. In one embodiment the barrier layer comprises anon-toxic edible polymer, edible pigment particles, an edible polymerplasticizer, and a surfactant. Materials include, for example and notlimitation, materials described in U.S. Pat. No. 4,543,370 (Colorcon),incorporated herein by reference. Exemplary barrier layers includeOPADRY®, which is available from Colorcon (West Point Pa. USA); OPADRYII® which is available from Colorcon (West Point Pa. USA) and comprisesHPMC, titanium dioxide, plasticizer and other components; and polyvinylalcohol-polyethylene glycol copolymer marketed as Kollicoat® IR (BASF).Suitable barrier layers, for illustration and not limitation, includeKollicoat® IR (a polyvinyl alcohol-polyethylene glycol graft copolymer)and Kollicoat IR White® both manufactured by BASF Aktiengesellschaft(Ludwigshafen, Germany). The thickness of the barrier layer can varyover a wide range, but is generally in the range 20 to 3,000 microns,such as on the order of about 25 to 250 microns. Preferably the barrierlayer retards the release of famotidine by less than 5 minutes,preferably less than 4 minutes and more preferably by less than 3minutes.

A. Famotidine Compartment Pharmaceutical compositions in accordance withthe present invention comprise a famotidine compartment structured as acore comprising a therapeutically effective amount of famotidine. Thecore can include both famotidine and, optionally, one or morepharmaceutically acceptable excipients.

The core can include an amount of famotidine suitable, for example, forthe methods of treatment described hereinafter. For example, the corecan comprise from 24 mg to 28 mg of famotidine, from 12 mg to 14 mg offamotidine, or the like, in various formulations consistent with thepresent invention. In some embodiments, the famotidine compartmentcomprises a core comprising about 13.3 mg or about 26.6 mg offamotidine.

B. Ibuprofen Compartment

Pharmaceutical compositions of the present invention further comprise anibuprofen compartment comprising a therapeutically effective amount ofibuprofen surrounding and, in some embodiments, in direct physicalcontact with the famotidine core described above. The surroundingportion of ibuprofen is, in some embodiments, in direct physical contactwith the core over a surface area defined by the dimensions of the core,which does not exceed an area calculated from Formula (I).

The ibuprofen compartment can include an amount of ibuprofen suitable,for example, for the methods of treatment described hereinafter, and,optionally, one or more pharmaceutically acceptable excipients. Forexample, the ibuprofen shell can comprise from 750 mg to 850 mg ofibuprofen, from 575 mg to 625 mg of ibuprofen, from 375 mg to 425 mg ofibuprofen, or the like, in various formulations consistent with thepresent invention. In some embodiments, the ibuprofen compartmentcomprises a surrounding portion comprising from 775 mg to 825 mg ofibuprofen, or, in one embodiment, 800 mg of ibuprofen. In otherembodiments, the compositions and/or unit dosage forms of the presentinvention comprise ibuprofen and famotidine in a ratio of from about29:1 to about 31:1, and preferably in a ratio of about 30:1. In someembodiments, the ibuprofen is in the form of Ibuprofen DC 85™.

C. Surface Area of Direct Physical Contact

The reduction, and in some embodiments, minimization, of the surfacearea of the core, or of direct physical contact between the activepharmaceutical ingredients, provides unexpected advantages in theformulation of stable pharmaceutical compositions of famotidine andibuprofen. The reduction and/or minimization of the surface area of thecore, or of direct physical contact between the incompatible activepharmaceutical ingredients, is achieved through control of the geometryof the famotidine compartment of unit dosage forms in accordance withthe present invention.

As will be appreciated, a given amount of material (e.g., famotidineplus one or more excipients) occupies a specific volume defined by thedensity of the material. In the case of pharmaceutical compositions ofthe present invention, the density of the material will, in part, bedetermined by the pressure applied to compress the material into thefamotidine compartment (i.e., the core), and more specifically by thedimensions of the equipment used in the manufacturing process. Tabletmanufacturing techniques known in the art for other materials can beemployed to prepare the famotidine compartment with the geometry beingdefined by the shape of the punches used to compress the material (i.e.,famotidine plus one or more optional excipients).

The surface area of the core and the corresponding surface area ofdirect physical contact can be limited or, in some cases, minimized, byselecting a core geometry that can contain the desired quantity offamotidine and optional excipients in a volume that has a correspondingsurface area that meets the criteria described above with reference toFormula (I). Although the addition of excipients increases the volumeand the corresponding surface area of the famotidine core, theexcipients may by useful, as described in greater detail hereinafter, toimpart particular qualities to the famotidine component of thepharmaceutical composition, or to provide a beneficial characteristicthat may be desirable for further processing to prepare thetablet-in-tablet formulation. In some embodiments, the famotidinecomponent has a geometry that is substantially cylindrical in shape. Inother embodiments, the famotidine component has a geometry that issubstantially spherical in shape.

Without intending to limit the scope of the present invention, thefollowing examples of surface area calculations are provided toillustrate this particular feature of the claimed invention. In anembodiment of the invention in which the famotidine compartment or corecomprises about 26.6 mg of famotidine, the famotidine and thesurrounding portion of ibuprofen are in direct physical contact over asurface area that does not exceed an area calculated from Formula (I),i.e., 25 mm²+3.75 mm² ·26.6=124.75 mm². Similarly, a famotidinecompartment comprising about 13.3 mg of famotidine will have an area ofdirect physical contact not to exceed 74.88 mm²; i.e., 25 mm²·+3.75 mm²·13.3=74.88 mm².

In other embodiments, the selection of geometry can further limit thesurface area of direct physical contact between the famotidine core andthe surrounding portion of ibuprofen. For example, if the core issubstantially cylindrical in shape, and the radius of the cylinderapproximates the length, about 26.6 mg of famotidine can be contained ina volume whose surface area does not exceed 120 mm², 119 mm², 118 mm²,117 mm², 116 mm², 115 mm², 114 mm², 113 mm², 112 mm², 111 mm², or 110mm². In still other embodiments, the selection of geometry can be usedto minimize the surface area of direct physical contact between thefamotidine core and the surrounding portion of ibuprofen. In thesecases, the core is substantially spherical in shape and can compriseabout 26.6 mg of famotidine, for example, in a volume whose surface areadoes not exceed 100 mm², 99 mm², 98 mm², 97 mm², 96 mm², 95 mm², 94 mm²,93 mm², 92 mm², 91 mm², or 90 mm².

Various exemplary, non-limiting embodiments of the famotidine core inaccordance with the present invention are provided in Table 1.

TABLE 1 Famotidine Core: Dimensions, Volume and Surface Area Quan- ShapeRadius Length Volume Surface Area tity* Spherical 2.73 mm — 84.78 mm³ 93.33 mm² 26.6 mg Cylin- 3.00 mm 3.00 mm 84.78 mm³ 113.04 mm² 26.6 mgdrical Spherical 2.79 mm — 90.43 mm³  97.42 mm² 26.6 mg Cylin- 3.00 mm3.20 mm 90.43 mm³ 116.81 mm² 26.6 mg drical Spherical 2.70 mm — 81.98mm³  91.22 mm² 26.6 mg Cylin- 2.95 mm 3.00 mm 81.98 mm³ 110.23 mm² 26.6mg drical Spherical 2.17 mm —  42.5 mm³  58.87 mm² 13.3 mg Cylin- 2.39mm 2.39 mm  42.5 mm³  71.44 mm² 13.3 mg drical Spherical 1.72 mm — 21.25mm³  37.11 mm² 6.65 mg Cylin- 1.89 mm 1.89 mm 21.25 mm³  44.96 mm² 6.65mg drical *Quantity of famotidine; core also includes excipients asidentified in Example 1 in relative proportion.

As will be appreciated, a core having a particular volume defined by itsdimensions will have an upper limit in regard to the quantity ofexcipients that can be included with a desired quantity of famotidine.In various embodiments, the ratio of famotidine to excipients in thecore does not exceed from about 1:1.89 to about 1:2.36, from about1:1.89 to about 1:2.84, from about 1:1.89 to about 1:3.31, or from about1:1.89 to about 1:3.78. The excipients can include any one or more ofthe excipients identified in Example 1 herein, or other excipients knownto those of skill in the art that are suitable for the specificapplication of the present invention.

D. Excipients

A variety of excipients may be combined with famotidine and/or ibuprofenin their respective compartments of the pharmaceutical compositions ofthe present invention. As mentioned above, the provision of variousexcipients may be useful to impart particular qualities to either thefamotidine component or the ibuprofen component of the pharmaceuticalcomposition, or to provide a beneficial characteristic that may bedesirable for processing to prepare the tablet-in-tablet formulation.Pharmaceutically acceptable excipients useful in compositions of thepresent invention can include binders, lubricants, diluents,disintegrants, and glidants, or the like, as known in the art. See e.g.,HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS, 2004, Ed.Sarfaraz K Niazi, CRC Press; HANDBOOK OF PHARMACEUTICAL ADDITIVES,SECOND EDITION, 2002, compiled by Michael and Irene Ash, Synapse Books;and REMINGTON SCIENCE AND PRACTICE OF PHARMACY, 2005, David B. Troy(Editor), Lippincott Williams & Wilkins.

Binders useful in compositions of the present invention are thoseexcipients that impart cohesive qualities to components of apharmaceutical composition. Commonly used binders include, for example,starch; sugars, such as, sucrose, glucose, dextrose, and lactose;cellulose derivatives such as powdered cellulose, microcrystallinecellulose, silicified microcrystalline cellulose (SMCC),hydroxypropylcellulose, low-substituted hydroxypropylcellulose,hypromellose (hydroxypropylmethylcellulose); and mixtures of these andsimilar ingredients.

Lubricants can be added to components of the present compositions toreduce sticking by a solid formulation to the equipment used forproduction of a unit does form, such as, for example, the punches of atablet press. Examples of lubricants include magnesium stearate andcalcium stearate. Other lubricants include, but are not limited to,aluminum-stearate, talc, sodium benzoate, glyceryl mono fatty acid(e.g., glyceryl monostearate from Danisco, UK), glyceryl dibehenate(e.g., CompritolATO888™ Gattefosse France), glyceryl palmito-stearicester (e.g., Precirol™, Gattefosse France), polyoxyethylene glycol (PEG,BASF) such as PEG 4000-8000, hydrogenated cotton seed oil or castor seedoil (Cutina H R, Henkel) and others.

Diluents can be added to components of a pharmaceutical composition toincrease bulk weight of the material to be formulated, e.g. tabletted,in order to achieve the desired weight.

Disintegrants useful in the present compositions are those excipientsincluded in a pharmaceutical composition in order to ensure that thecomposition has an acceptable disintegration rate in an environment ofuse. Examples of disintegrants include starch derivatives (e.g., sodiumcarboxymethyl starch and pregelatinized corn starch such as starch 1500from Colorcon) and salts of carboxymethylcellulose (e.g., sodiumcarboxymethylcellulose), crospovidone (cross-linked PVPpolyvinylpyrrolidinone (PVP), e.g., Polyplasdone™ from ISP or Kollidon™from BASF).

Glidants refer to excipients included in a pharmaceutical composition tokeep the component powder flowing as a tablet is being made, preventingformation of lumps. Nonlimiting examples of glidants are colloidalsilicon dioxides such as CAB-O-SIL™ (Cabot Corp.), SYLOID™, (W.R. Grace& Co.), AEROSIL™ (Degussa), talc, and corn starch.

E. Stability of Tablet-in-Tablet Compositions

Tablet-in-tablet compositions of the present invention comprising afamotidine compartment and an ibuprofen compartment surrounding and, insome embodiments, in direct physical contact with the famotidinecompartment are stable for extended periods under “forced degradation”conditions of elevated temperature and relative humidity. For example,compositions of famotidine and ibuprofen prepared as described in the“Examples” section, hereinbelow, exhibit unexpectedly dramaticimprovements in stability at 40° C. and 75% relative humidity, relativeto alternative designs (e.g., barrier-coated famotidinemultiparticulates in a matrix comprising ibuprofen). Moreover, using thedesign of the present invention, the barrier layer can be omittedwithout sacrificing stability.

“Forced degradation” conditions (e.g., 40° C. and 75% relative humidity)are used to evaluate the long-term storage stability of a pharmaceuticalingredient or composition. In general terms, a stable composition is onewhich comprises the pharmaceutically active ingredients in an amount,for example 95%, relative to the amount initially present in theparticular composition. Stability may be determined, using forceddegradation or other methods, for periods of 1 week, 1 month, 2 months,3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months,18 months, 24 months, 30 months, 36 months, longer.

Stability may also be determined by the presence and quantity ofimpurities. A principal degradant produced through the chemicalinteraction of famotidine and ibuprofen in compositions of the presentinvention is sulfamide. A quantitative determination of the presence ofsulfamide in a unit dose form of the present invention held under forceddegradation conditions for a period of time yields valuable informationabout the long-term stability of the composition under ordinary (e.g.,room temperature) storage conditions.

Assays for evaluating the stability of a pharmaceutical composition,such as those described in the present invention, are known in thepharmaceutical arts. For example, one can determine the percentage ofactive pharmaceutical ingredients present in a given composition, aswell as the presence and percentage of impurities, through the use ofstandard analytical techniques.

III. Methods of Making Tablet-in-Tablet Compositions

It is within the ability of one of ordinary skill in the art, guided bythe present disclosure and with reference to the pharmaceuticalliterature, to prepare and manufacture unit dosage forms of theinvention in accordance with the methods of the invention.

In one embodiment, the unit dosage form comprises a tablet dosage formhaving a famotidine core and a surrounding layer containing ibuprofen.Optionally, the tablet is coated by one or more over-coating layers, forexample, to improve appearance, taste, swallowability, or for otherreasons. In another embodiment, a barrier layer is interposed betweenthe famotidine core and the ibuprofen shell. Methods for formulation andmanufacture of pharmaceutical unit dose forms are known in the art, see,e.g., HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS, 2004, Ed.Sarfaraz K Niazi, CRC Press; HANDBOOK OF PHARMACEUTICAL ADDITIVES,SECOND EDITION, 2002, compiled by Michael and Irene Ash, Synapse Books;and REMINGTON SCIENCE AND PRACTICE OF PHARMACY, 2005, David B. Troy(Editor), Lippincott Williams & Wilkins. One of ordinary skill in theart guided by this disclosure will be able to make a variety of suitableoral unit dose forms.

In general, a tablet-in-tablet composition is produced by firstpreparing a tablet “core” from a first component, and then applying a“shell” (e.g., through compression, or the like) of a second componentin a manner such that the finished formulation comprises the coresurrounded by the shell. In embodiments in which a barrier layer isinterposed between the famotidine core and the ibuprofen shell, thebarrier may be applied to the “core” by, e.g., spray coating, or thelike.

As noted above, in some embodiments, the tablets are coated for oraladministration to make the tablet easier to swallow, to mask taste, forcosmetic reasons, or for other reasons. Coating of tablets and capletsis well known in the art. Coating systems are typically mixtures ofpolymers, plasticisers, coloring agents and other excipients, which canbe stirred into water or an organic solvent to produce a dispersion forthe film coating of solid oral dosage forms such as tablets. Often, areadily soluble film is used. Materials that can be used for readilysoluble films include cellulose derivatives (such as hydroxypropylmethylcellulose) or amino-alkylmethacrylate copolymers (e.g. Eudragit™E).Suitable coat layers, for illustration and not limitation, includeKollicoat® IR (a polyvinyl alcohol-polyethylene glycol graft copolymer)and Kollicoat IR White®, both manufactured by BASF Aktiengesellschaft(Ludwigshafen, Germany).

IV. Methods of Treatment

In one aspect, the present invention is directed to methods of treatingsubjects in need of ibuprofen and famotidine treatment. Methodsapplicable to the present invention are described in co-pendingapplication Ser. No. 11/779,204, filed Jul. 17, 2007, and incorporatedherein by reference. Subjects in need of ibuprofen and famotidinetreatment include those individuals at elevated risk for developing anNSAID-induced ulcer (i.e., the subject is more susceptible than theaverage individual to development of an ulcer when under treatment withan NSAID). More generally, subjects in need of ibuprofen and famotidinetreatment are those individuals who receive a therapeutic benefit fromadministration of ibuprofen and famotidine.

Ibuprofen is indicated for treatment of mild to moderate pain,dysmenorrhea, inflammation, and arthritis. In one embodiment, thesubject in need of ibuprofen treatment with a dosage form of theinvention is under treatment for a chronic condition. For example andwithout limitation, a subject in need of ibuprofen treatment may be anindividual with rheumatoid arthritis, an individual with osteoarthritis,an individual suffering from chronic pain (e.g., chronic low back pain,chronic regional pain syndrome, chronic soft tissue pain), or anindividual suffering from a chronic inflammatory condition. In general,a subject under treatment for a chronic condition requires ibuprofentreatment for an extended period, such as at least one month, at leastfour months, at least six months, or at least one year, and at leastsome of these subjects can benefit from receiving famotidine incombination with ibuprofen during such treatment period. In anotherembodiment, the subject in need of ibuprofen treatment is undertreatment for a condition that is not chronic, such as acute pain,dysmenorrhea or acute inflammation and can benefit from receivingfamotidine in combination with ibuprofen during such treatment.

In certain embodiments oral dosage forms of the invention are formulatedso that release of both active pharmaceutical ingredients (APIs) occurs(or begins to occur) at about the same time. “At about the same time”means that release of one API begins within 5 minutes of the beginningof release of the second API, sometimes with 4 minutes, sometimes within3 minutes, sometimes within 2 minutes, and sometimes essentiallysimultaneously. “At about the same time” can also mean that release ofone API begins before release of the second API is completed. That is,the dosage form is not designed so that one of the APIs is releasedsignificantly later than the other API. To achieve this, combinations ofexcipients (which may include one or more of a binder, a lubricant, adiluent, a disintegrant, a glidant and other componants) are selectedthat do not substantially retard release of an API. See e.g., HANDBOOKOF PHARMACEUTICAL MANUFACTURING FORMULATIONS, 2004, Ed. Sarfaraz KNiazi, CRC Press; HANDBOOK OF PHARMACEUTICAL ADDITIVES, SECOND EDITION,2002, compiled by Michael and Irene Ash, Synapse Books; and REMINGTONSCIENCE AND PRACTICE OF PHARMACY, 2005, David B. Troy (Editor),Lippincott Williams & Wilkins.

In the unit dose forms of the invention, both the famotidine oribuprofen are formulated for immediate release, and not for releaseprofiles commonly referred to as delayed release, sustained release, orcontrolled release. For example, in one embodiment, the unit dosage formis formulated so that famotidine and ibuprofen are released rapidlyunder neutral pH conditions (e.g., an aqueous solution at about pH 6.8to about pH 7.4, e.g., pH 7.2). In this context, “rapidly” means thatboth APIs are significantly released into solution within 20 minutesunder in vitro assay conditions. In some embodiments both APIs aresignificantly released into solution within 15 minutes under in vitroassay conditions. In this context, “significantly released” means thatat least about 60% of the weight of the API in the unit dosage form isdissolved, or at least about 75%, or at least about 80%, or at leastabout 90%, and sometimes at least about 95%. In one embodiment, bothfamotidine and ibuprofen are at least 95% released in 30 minutes.

Dissolution rates may be determined using known methods. Generally an invitro dissolution assay is carried out by placing thefamotidine-ibuprofen unit dosage form(s) (e.g., tablet(s)) in a knownvolume of dissolution medium in a container with a suitable stirringdevice. Samples of the medium are withdrawn at various times andanalyzed for dissolved active substance to determine the rate ofdissolution. Dissolution may be measured, for example, as described foribuprofen in the USP or, alternatively, as described for famotidine inthe USP. Briefly, in this exemplary method, the unit dose form (e.g.,tablet) is placed in a vessel of a United States Pharmacopeiadissolution apparatus II (Paddles) containing 900 ml dissolution mediumat 37° C. The paddle speed is 50 RPM. Independent measurements are madefor at least three (3) tablets. In one suitable in vitro assay,dissolution is measured using a neutral dissolution medium such as 50 mMpotassium phosphate buffer, pH 7.2 (“neutral conditions”).

Alternatively, dissolution rates may be determined under low pHconditions. Release under low pH conditions can be measured using the invitro dissolution assay described above, but using, for example, 50 mMpotassium phosphate buffer, pH 4.5, as a dissolution medium. As used inthis context, the APIs are released rapidly at low pH when a substantialamount of both APIs is released into solution within 60 minutes underlow pH assay conditions. In some embodiments, a substantial amount ofboth APIs is released into solution within 40 minutes under low pH assayconditions. In some embodiments, a substantial amount of both APIs isreleased into solution within 20 minutes under low pH assay conditions.In some embodiments, a substantial amount of both APIs is released intosolution within 10 minutes under low pH assay conditions. In thiscontext, a “substantial amount” means at least 15%, or at least 20%, orat least 25% of ibuprofen is dissolved and at least 80%, or at least85%, or at least 90% of famotidine is dissolved.

In some cases, dosage forms of the present invention are designed forthree times per day (TID) administration of famotidine and ibuprofen toa patient in need thereof.

When administered to avoid or mitigate the ulcerogenic effects oflong-term NSAID therapy, famotidine has been administered at 40 mg BID(see Taha et al., 1996, supra). However, as described in co-pendingapplication Ser. Nos. 11/489,275 and 11/489,705, both filed Jul. 18,2006, and incorporated herein by reference, it has now been determinedusing pharmacokinetic modeling and in clinical trials, that TIDadministration of famotidine provides a therapeutic effect superior tothat achieved by BID dosing. For example, on average, TID administrationof famotidine results in intragastric pH higher than 3.5 for a greaterproportion of the dosing cycle than conventional BID dosing.

Treatment using the methods of TID administration also results inreduced interpatient variability with respect to gastric pH in apopulation of patients receiving an ibuprofen-famotidine combinationtreatment. This reduction increases predictability of the treatment andreduces the likelihood that any particular patient will experiencedetrimental gastric pH in the course of ibuprofen-famotidine combinationtherapy.

Thus, in another aspect, the present invention provides a method foradministration of ibuprofen to a patient in need of ibuprofen treatmentby administering an oral dosage form comprising a therapeuticallyeffective amount of ibuprofen and a therapeutically effective amount offamotidine, wherein the oral dosage form comprises a tablet-in-tabletformulation for administration three times per day (TID).

EXAMPLES

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Example 1

A tablet-in-tablet composition of famotidine and ibuprofen according tothe present invention can be prepared by first preparing a famotidinecore, which is then surrounded by an ibuprofen shell and an optionalover-coating. The famotidine core is prepared by (i) combining 26.6 mgfamotidine, 10.0 mg lactose monohydrate, 34.6 mg microcrystallinecellulose, 4.0 mg croscarmellose sodium, and 0.4 mg colloidal silicondioxide in a suitably sized V-blender; (ii) mixing the combinedingredients for approximately ten minutes; (iii) discharging the blendedmaterials from the blender and passing them through a #20 mesh screen;(iv) transferring the screened material back into the V-blender andmixing for approximately ten additional minutes; (vi) passing 1.2 mgmagnesium stearate through a #30 mesh screen; (vii) adding the screenedmagnesium stearate to the blended material in the V-blender and mixingfor approximately three additional minutes; (viii) discharging theblended material into a polyethylene lined container; and (ix)compressing the blended material into a tablet (i.e., a famotidine core)on a rotary tablet press using 0.2187″ plain round SC (standard concaveround) tooling. The famotidine core is then centered in atablet-in-tablet composition by compressing 941.2 mg of Ibuprofen DC 85™(comprises 800 mg of ibuprofen) around the famotidine core using atablet press and 0.4100″×0.7500″ oval plain tooling. Thetablet-in-tablet is then preferably over-coated by placement in asuitably sized perforated coating pan to which a dispersion of Opadry II(Colorcon, Inc., West Point, Pa.) in water is added to coat thetablet-in-tablet to a weight gain of 3%.

A summary of the materials used in the tablet-in-tablet compositiondescribed in Example 1 are provided in Table 2 below.

TABLE 2 Formulation Components of Exemplary Tablet-in-Tablet Unit DosageForm Item Material % w/w mg/Tab-in-Tab Function 1 Famotidine 2.54 26.6API 2 Lactose monohydrate 0.95 10.0 Binder (DCL 21) 3 Microcrystalline3.30 34.6 Binder cellulose (Avicel PH102) 4 Croscarmellose sodium 0.384.0 Disintegrant (Ac-di-sol) 5 Colloidal silicon dioxide 0.04 0.4Glidant (Cab-o-sil M5P) 6 Magnesium stearate 0.11 1.2 Lubricant 7Ibuprofen granules 89.75 941.2 API (DC-85)* 8 Opadry II 2.93 30.7Over-coat (85F18422 White) 9 Purified Water — q.s. Process aid Total —100.00 1048.7 — *Contains 800 mg of ibuprofen.

Example 2

A tablet-in-tablet composition of famotidine and ibuprofen in accordancewith the present invention, and which includes a barrier layerinterposed between the active pharmaceutical ingredients can be preparedas described in Example 1, with the following modification. Followingpreparation of the famotidine core by compressing the blended materialinto a tablet (i.e., step (ix)), the tablet core is coated with abarrier layer by placement in a suitably sized perforated coating pan towhich a dispersion of Opadry (YS-1-7003) (Colorcon) in water is added tocoat the tablet core to a weight gain of 5%. With reference to thematerials identified in Table 2, a weight gain of 5% requires about 3.8mg of Opadry.

Example 3

Stability of three distinct famotidine plus ibuprofen formulations wasevaluated under “forced degradation” conditions of 40° C. and 75%relative humidity to assess the viability of the different combinationsof the active pharmaceutical ingredients. Surprisingly, atablet-in-tablet formulation in accordance with the present inventionexhibited remarkably improved stability, as shown in Table 3 below, ascompared to both a multiparticulate formulation and a bilayerformulation, each of which relies on the presence of a barrier betweenthe famotidine and ibuprofen to reduce chemical interaction anddegradation of the active pharmaceutical ingredients.

The multiparticulate formulation comprises an ibuprofen matrix intowhich are dispersed a plurality of famotidine beads. Each famotidinebead consists of a microcrystalline cellulose core surrounded by a layerof famotidine which is coated with a protective barrier layer (e.g.,Opadry). A description of the process of making such beads is providedin Example 9 of co-pending application Ser. No. 11/779,204, filed Jul.17, 2007. The bilayer tablet formulation similarly comprises a layer offamotidine beads sandwiched together with a layer of ibuprofen.

TABLE 3 1 Month Stability of Famotidine + Ibuprofen Compositions (@ 40°C. and 75% Relative Humidity) Tablet-in- Tablet-in- Tablet Tablet Multi-Formulation Formulation Stability particulate Bilayer (Direct (BarrierIndicator Formulation Formulation Contact)^(†) Coated)^(††) % Sulfamide3.55 0.91 0.56 0.00 Ibuprofen 0.23 2.01 0.00 0.00 Impurities** Total4.90 3.00 0.70 0.00 Impurities % Ibuprofen* 100.3 100.5 99.5 100.8 %Famotidine* 95.5 103.2 94.6 96.7 *Calculated from initial sampleassessment; each formulation includes 26.6 mg famotidine and 800 mgibuprofen. **Ibuprofen impurities comprise components attributable tothe degradation of ibuprofen. ^(†)Prepared according to the proceduredescribed in Example 1. ^(††)Prepared according to the proceduredescribed in Example 2.

As shown in Table 2, above, the tablet-in-tablet formulation inaccordance with the present invention shows a markedly improvedstability profile, as compared with the multiparticulate and bilayerformulations of the same chemically incompatible active ingredients, interms of both the presence of sulfamide, the principal famotidinedegradant, as well as total impurities. In the multiparticulateformulation, the issue of chemical incompatibility is addressed by thebarrier layer surrounding each famotidine bead dispersed throughout theibuprofen matrix. Similarly, in the bilayer formulation, barrier-coatedfamotidine beads make up the famotidine layer of the bilayerconstruction.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A pharmaceutical composition comprising: a first layer comprisingfrom 750 mg to 850 mg ibuprofen as an active pharmaceutical ingredientand at least one excipient, and a second layer comprising from 24 mg to28 mg famotidine as an active pharmaceutical ingredient and at least oneexcipient, wherein the active pharmaceutical ingredients are in directcontact, wherein the pharmaceutical composition is in the form of atablet, provided that if the pharmaceutical composition is atablet-in-tablet formulation, the first layer completely surrounds thesecond layer, wherein the pharmaceutical composition is formulated forimmediate release, and wherein none of the pharmaceutical composition,the first layer, the second layer, the famotidine, or the ibuprofen isenterically coated or formulated for sustained or delayed release,wherein the pharmaceutical composition is formulated so that release ofthe ibuprofen active pharmaceutical ingredient and the famotidine activepharmaceutical ingredient begins to occur at about the same time,wherein the famotidine is not present as barrier coated famotidinemultiparticulates dispersed in an ibuprofen matrix, and wherein no morethan about 1% of a sulfamide is present when the composition is storedat 40° C. and 75% relative humidity for a period of one month.
 2. Thepharmaceutical composition of claim 1, wherein the composition comprises800 mg ibuprofen and 26.6 mg famotidine.
 3. The pharmaceuticalcomposition of claim 1, wherein no more than about 1% of a sulfamide ispresent when the composition is stored at 40° C. and 75% relativehumidity for a period of three months.
 4. The pharmaceutical compositionof claim 1, wherein no more than about 1% of a sulfamide is present whenthe composition is stored at 40° C. and 75% relative humidity for aperiod of six months.
 5. The pharmaceutical composition of claim 1,wherein no more than about 0.6% of a sulfamide is present when thecomposition is stored at 40° C. and 75% relative humidity for a periodof one month.
 6. The pharmaceutical composition of claim 1, wherein nomore than about 0.6% of a sulfamide is present when the composition isstored at 40° C. and 75% relative humidity for a period of three months.7. The pharmaceutical composition of claim 1, wherein no more than about0.6% of a sulfamide is present when the composition is stored at 40° C.and 75% relative humidity for a period of six months.
 8. Thepharmaceutical composition of claim 1, wherein the composition is atablet-in-tablet formulation wherein the first layer completelysurrounds the second layer.
 9. The pharmaceutical composition of claim1, wherein the composition is a bilayer tablet.
 10. A pharmaceuticalcomposition comprising: a first layer comprising from 750 mg to 850 mgibuprofen as an active pharmaceutical ingredient and at least oneexcipient, and a second layer comprising from 24 mg to 28 mg famotidineas an active pharmaceutical ingredient and at least one excipient,wherein the active pharmaceutical ingredients are in direct contact,wherein the pharmaceutical composition is in the form of a tablet,provided that if the pharmaceutical composition is a tablet-in-tabletformulation, the first layer completely surrounds the second layer,wherein the pharmaceutical composition is formulated for immediaterelease, and wherein none of the pharmaceutical composition, the firstlayer, the second layer, the famotidine, or the ibuprofen is entericallycoated or formulated for sustained or delayed release, wherein thepharmaceutical composition is formulated so that release of theibuprofen active pharmaceutical ingredient and the famotidine activepharmaceutical ingredient begins to occur at about the same time,wherein the famotidine is not present as barrier coated famotidinemultiparticulates dispersed in an ibuprofen matrix, and wherein no morethan about 1% of a sulfamide is present when the composition is storedat room temperature for a period of three months.
 11. The pharmaceuticalcomposition of claim 10, wherein the composition comprises 800 mgibuprofen and 26.6 mg famotidine.
 12. The pharmaceutical composition ofclaim 10, wherein no more than about 1% of a sulfamide is present whenthe composition is stored at room temperature for a period of sixmonths.
 13. The pharmaceutical composition of claim 10, wherein no morethan about 1% of a sulfamide is present when the composition is storedat room temperature for a period of nine months.
 14. The pharmaceuticalcomposition of claim 10, wherein no more than about 1% of a sulfamide ispresent when the composition is stored at room temperature for a periodof 12 months.
 15. The pharmaceutical composition of claim 10, wherein nomore than about 1% of a sulfamide is present when the composition isstored at room temperature for a period of 18 months.
 16. Thepharmaceutical composition of claim 10, wherein no more than about 1% ofa sulfamide is present when the composition is stored at roomtemperature for a period of 24 months.
 17. The pharmaceuticalcomposition of claim 10, wherein no more than about 1% of a sulfamide ispresent when the composition is stored at room temperature for a periodof 36 months.
 18. The pharmaceutical composition of claim 10, wherein nomore than about 0.6% of a sulfamide is present when the composition isstored at room temperature for a period of three months.
 19. Thepharmaceutical composition of claim 10, wherein no more than about 0.6%of a sulfamide is present when the composition is stored at roomtemperature for a period of six months.
 20. The pharmaceuticalcomposition of claim 10, wherein no more than about 0.6% of a sulfamideis present when the composition is stored at room temperature for aperiod of nine months.
 21. The pharmaceutical composition of claim 10,wherein no more than about 0.6% of a sulfamide is present when thecomposition is stored at room temperature for a period of 12 months. 22.The pharmaceutical composition of claim 10, wherein no more than about0.6% of a sulfamide is present when the composition is stored at roomtemperature for a period of 18 months.
 23. The pharmaceuticalcomposition of claim 10, wherein no more than about 0.6% of a sulfamideis present when the composition is stored at room temperature for aperiod of 24 months.
 24. The pharmaceutical composition of claim 10,wherein no more than about 0.6% of a sulfamide is present when thecomposition is stored at room temperature for a period of 36 months. 25.The pharmaceutical composition of claim 10, wherein the composition is atablet-in-tablet formulation wherein the first layer completelysurrounds the second layer.
 26. The pharmaceutical composition of claim10, wherein the composition is a bilayer tablet.
 27. A pharmaceuticalcomposition comprising: a first layer comprising from 750 mg to 850 mgibuprofen as an active pharmaceutical ingredient and at least oneexcipient, and a second layer comprising from 24 mg to 28 mg famotidineas an active pharmaceutical ingredient and at least one excipient,wherein the pharmaceutical composition is in the form of a tablet,provided that if the pharmaceutical composition is a tablet-in-tabletformulation, the first layer completely surrounds the second layer,wherein the pharmaceutical composition is formulated for immediaterelease, and wherein none of the pharmaceutical composition, the firstlayer, the second layer, the famotidine, or the ibuprofen is entericallycoated or formulated for sustained or delayed release, wherein thepharmaceutical composition is formulated so that release of theibuprofen active pharmaceutical ingredient and the famotidine activepharmaceutical ingredient begins to occur at about the same time,wherein the famotidine is not present as barrier coated famotidinemultiparticulates dispersed in an ibuprofen matrix, wherein thefamotidine active pharmaceutical ingredient and the ibuprofen activepharmaceutical ingredient have a surface area of direct physical contactthat does not exceed 130 mm², and wherein no more than about 1% of asulfamide is present when the composition is stored at 40° C. and 75%relative humidity for a period of one month.
 28. The pharmaceuticalcomposition of claim 27, wherein the composition comprises 800 mgibuprofen and 26.6 mg famotidine.
 29. The pharmaceutical composition ofclaim 27, wherein no more than about 1% of a sulfamide is present whenthe composition is stored at room temperature for a period of sixmonths.
 30. The pharmaceutical composition of claim 27, wherein no morethan about 1% of a sulfamide is present when the composition is storedat room temperature for a period of nine months.
 31. The pharmaceuticalcomposition of claim 27, wherein no more than about 1% of a sulfamide ispresent when the composition is stored at room temperature for a periodof 12 months.
 32. The pharmaceutical composition of claim 27, wherein nomore than about 1% of a sulfamide is present when the composition isstored at room temperature for a period of 18 months.
 33. Thepharmaceutical composition of claim 27, wherein no more than about 1% ofa sulfamide is present when the composition is stored at roomtemperature for a period of 24 months.
 34. The pharmaceuticalcomposition of claim 27, wherein no more than about 1% of a sulfamide ispresent when the composition is stored at room temperature for a periodof 36 months.
 35. The pharmaceutical composition of claim 27, wherein nomore than about 0.6% of a sulfamide is present when the composition isstored at room temperature for a period of three months.
 36. Thepharmaceutical composition of claim 27, wherein no more than about 0.6%of a sulfamide is present when the composition is stored at roomtemperature for a period of six months.
 37. The pharmaceuticalcomposition of claim 27, wherein no more than about 0.6% of a sulfamideis present when the composition is stored at room temperature for aperiod of nine months.
 38. The pharmaceutical composition of claim 27,wherein no more than about 0.6% of a sulfamide is present when thecomposition is stored at room temperature for a period of 12 months. 39.The pharmaceutical composition of claim 27, wherein no more than about0.6% of a sulfamide is present when the composition is stored at roomtemperature for a period of 18 months.
 40. The pharmaceuticalcomposition of claim 27, wherein no more than about 0.6% of a sulfamideis present when the composition is stored at room temperature for aperiod of 24 months.
 41. The pharmaceutical composition of claim 27,wherein no more than about 0.6% of a sulfamide is present when thecomposition is stored at room temperature for a period of 36 months. 42.The pharmaceutical composition of claim 27, wherein the composition is atablet-in-tablet formulation wherein the first layer completelysurrounds the second layer.
 43. The pharmaceutical composition of claim27, wherein the composition is a bilayer tablet.